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Molecular mechanisms Flashcards

1
Q

What is the function of micro RNA (miRNA)?

A

Master regulator of gene function

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2
Q

What is RNA interference (RNAi)?

A

Post-transcriptional regulation by small interfering RNAs

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3
Q

In which organism were miRNA & RNAi discovered?

A

C. elegans

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4
Q

How is miRNA encoded into the genome?

A

In non-protein coding genes

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5
Q

How long are miRNA gene transcripts?

A

<200 nucleotides

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6
Q

What is the most important processor of unprocessed miRNA gene transcripts? What is its function?

A

DICER -> cuts pre-miRNA into smaller structures, ~20-22bp

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7
Q

What is the length of processed miRNA?

A

20-22 nucleotides

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8
Q

What happens when miRNA has been fully associated?

A

They associate with the RISC-complex

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9
Q

Which two structures make up the RISC complex?

A
  1. DICER
  2. Argonaut
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10
Q

What is the function of the RISC complex? What is the role in miRNA in the RISC complex?

A

The RISC complex interferes with mRNA and uses miRNA to recognize specific mRNA transcripts

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11
Q

What happens when there is perfect complementarity between RISC-associated miRNA and mRNA?

A

mRNA is completely degraded by DICER

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12
Q

What happens when there is partial complementarity between RISC-associated miRNA and mRNA?

A

RISC-complex associates with mRNA and blocks translation

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13
Q

How many % of mammalian DNA is regulated by miRNA?

A

60%

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14
Q

In which processes (among others) does miRNA regulation play a vital role? (3)

A
  1. Embryonic development
  2. Cancer (dysregulation)
  3. Other diseases
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15
Q

What is the main function of RNA interference (RNAi) in plants and invertebrates?

A

Forms a protection against viruses by recognizing dsRNA viral RNA and destroying it

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16
Q

How can invertebrates & plants build up immunological memory, despite their lack of an adaptive immune system?

A

They can incorporate viral transcripts into genome, using them to form miRNAs that can help the RISC-complex recognize and destroy invading virus RNA

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17
Q

Why are mammalian cells not reliant on RNAi for antiviral defence?

A

Mammals have potent antiviral IFN responses

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18
Q

In which two ways can miRNA be coded into the genome?

A
  1. Coding for a single pri-miRNA
  2. Polycistronic -> larger transcript, coding for multiple pri-miRNAs
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19
Q

What is pri-miRNA?

A

miRNA transcript before processing by DICER

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20
Q

By which three ways can miRNA-RISC complexes modify mRNA translation?

A
  1. Blocking translation of target mRNA
  2. Degrading target mRNA
  3. Deadenylate target mRNA
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21
Q

Which finding gives rise to the theory that miRNA has a broad function in immune regulation?

A

The fact that every immune cell type has a characteristic miRNA profile

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22
Q

What is the predominant miRNA in the liver?

A

miR-122

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23
Q

In which liver processes is miR-122 involved? (3)

A
  1. Metablism, specifically lipid homeostasis
  2. Stress responses
  3. Preventing cancer development
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24
Q

Which virus is reliant upon the presence of miR-122 for replication?

A

HCV

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25
Q

What is misregulation of miR-122 associated with?

A

Hepatocellular carcinoma

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26
Q

For which processes is HCV reliant on miR-122? (2)

A
  1. miR-122 binds to an untranslated region of the HCV viral +RNA and boosts translation
  2. HCV -RNA has miR-122 docking stations -> miR-122 binding leads to genome stability, more translation of viral protein & genome replication
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27
Q

Where does HCV enter the hepatocyte?

A

Tight junction

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28
Q

What is the effect of miR-122 docking to HCV -RNA? (3)

A
  1. Genome stability
  2. Stuctural alteration of the genome -> translation of more viral protein
  3. Genome replication & translation-replication swithc
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29
Q

What is a possible therapeutic application of miRNA?

A

Targeting/mimicking miRNA with antisense oligonucleotides (ASO)

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30
Q

What are LNA-molecules? What is their function?

A

LNA = locked nucleic acid = synthetic modified DNA, resistant to infection
Function: silencing miRNA

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31
Q

How long does the effect of antisense oligonucleotides aimed at miR-122 last?

A

60-80 days

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32
Q

What are the effects of antisense oligonucleotides aimed at miR-122 in HCV? (2)

A
  1. Reduction of plasma cholesterol (side effect)
  2. Dose-dependent, gradual decrease of HCV RNA levels
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33
Q

Why is antisense oligonucleotide therapy aimed at miR-122 not routinely used?

A

Antivirals for HCV make this treatment redundant

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34
Q

How can miRNAs be tranported through the body? What effect would this have?

A

Exosomes/microvesicles -> transport would allow miRNAs to modify the behaviour of other cells

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35
Q

In which forms can miRNA be released when a cell dies? (3)

A
  1. Part of apoptotic bodies
  2. Free RISC-miRNA complexes
  3. Free miRNA
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36
Q

How can miRNAs from food hypothesize human gene translation?

A

If food-derived miRNAs can survive the harsh environment of the gastrointestinal tract, they could possibly modify human gene translation

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37
Q

Where do ingested miRNAs accumulate?

A

The liver

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38
Q

What is the benefit of using miRNAs as a biomarker? (4)

A
  1. miRNAs are master regulators of gene biological processes
  2. Easy & sensitive detection of miRNAs is possible
  3. Highly stable & insensitive to degradation
  4. Highly cell-type specific expression patterns
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39
Q

Why is miR-122 a good biomarker for liver injury? (2)

A
  1. More sensitive to liver damage than ALAT
  2. miR-122 increases much faster after liver damage occurs (near-instant vs. ~24 hours)
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40
Q

What shows that miR-122 is a more sensitive marker of liver damage than ALAT?

A

ALAT is not elevated in chronic HCV patients, but miR-122 is

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41
Q

What are the applications of miRNA diagnostics in liver transplantation? (2)

A
  1. Assessment of liver quality prior to Tx
  2. Detection of rejection/damage post-Tx
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42
Q

What is the overall purpose of DNA repair?

A

Maintaining integrity of genetic material

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43
Q

Which DNA repair pathways are there? (6)

A
  1. Base excision repair (BER)
  2. Mismatch repair (MMR)
  3. Nucleotide excision repair (NER)
  4. Non-homologous end-joining (NHEJ)
  5. Alternative end-joining (AEJ)
  6. Homologous recombination (HR)
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44
Q

What determines which DNA repair pathway is used?

A

The type of DNA damage

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45
Q

Which forms of DNA damage are repaired by base excision repair (BER)? (4)

A
  1. Oxidation
  2. Uracil
  3. Abasic site
  4. Single strand break
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46
Q

Which agents can cause the types of DNA damage repaired by base excision repair? (4)

A
  1. ROS
  2. X-rays
  3. Alkylating agents
  4. Spontaneous reactions
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47
Q

Which forms of DNA damage are repaired by mismatch repair (MMR)? (4)

A
  1. A-G mismatch
  2. T-C mismatch
  3. Insertion
  4. Deletion
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48
Q

What causes the types of DNA damage repaired by mismatch repair (MMR)?

A

Replication erros

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49
Q

Which forms of DNA damage are repaired by nucleotide excision repair (NER)? (2)

A
  1. Bulky adducts
  2. Intrastrand crosslinks
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50
Q

What causes the types of DNA damage repaired by nucleotide excision repair (NER)? (3)

A
  1. UV-light
  2. Polycyclic aromatic hydrocarbons
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51
Q

Which mechanisms are responsible for the repair of double-strand DNA breaks (dsDNA breaks)?

A
  1. Non-homologous end-joining (NHEJ)
  2. Homologous recombination (HR)
  3. Alternative end-joining (AEJ)
52
Q

Which types of damage can cause dsDNA breaks? (3)

A
  1. X-rays
  2. Ionizing radiation
  3. Anti-tumour agents
53
Q

For which immunological cells is DNA repair especially crucial?

A

Lymphocytes -> rely on DNA breaks & repair to generate a diverse receptor repertoire

54
Q

Which processes of B- and/or T-cells rely on DNA repair?

A
  1. V(D)J-recombinatin -> both B- and T-cells
  2. Somatic hypermutation (SHM) -> B-cells
  3. Class switch recombination (CSR) -> B-cells
55
Q

Which DNA repair mechanisms is responsible for V(D)J recombination?

A

Non-homologous end-joining (NHEJ)

56
Q

Where does V(D)J-recombination of T-cells take place?

57
Q

Where does V(D)J-recombination of B-cells take place?

A

Bone marrow

58
Q

When does somatic hypermutation (SHM) of B-cells take place?

A

Germinal centre reaction

59
Q

Which DNA repair mechanisms are involved in somatic hypermutation (SHM)? (2)

A
  1. Mismatch repair (MMR)
  2. Base-excision repair (BER)
60
Q

Which DNA repair mechanisms are involved in class switch recombination (CSR)? (2)

A
  1. Non-homologous end-joining (NHEJ)
  2. Base-excision repair (BER)
  3. Alternative end-joining (AEJ)
61
Q

Where does class switch recombination (CSR) of B-cells take place?

A

Germinal centre reaction

62
Q

What is the purpose of V(D)J-recombination?

A

Achieving combinatorial diversity to expand the receptor repertoire

63
Q

What is the process of V(D)J-recombination to final receptor transcript? (4)

A
  1. D- to J-rearrangement (only heavy chain)
  2. V- to (D)J rearrangement
  3. Transcription
  4. Splicing to obtain final transcript
64
Q

Which mechanisms add extra diversity during V(D)J-recombination? (2)

A
  1. p-nucleotide addition
  2. n-nucleotide addition
65
Q

What is the process of DNA breakage & joining in V(D)J-recombination? (4)

A
  1. RAG1 & RAG2 form heterodimer to cut DNA
  2. RAG-complex recognizes conserved recombination signal sequences (RSS) and makes cuts here
  3. RAG makes hairpin in DNA to connect complementary strands
  4. Non-homologous recombination of the two strands: Artemis opens hairpin & DNA ligase ligates strands
66
Q

Which part of the DNA breakage & joining in V(D)J-recombination is specific?

A

The initiation of DNA breaks by RAG

67
Q

In which cell types is RAG expressed?

A

Tightly regulated to lymphocyte progenitors

68
Q

Why is RAG expression tightly regulated?

A

Unwarranted expression could cause DNA breaks when this is unwanted

69
Q

When is unwarranted expression of RAG especially dangerous?

A

During cell division

70
Q

Where can recombination signal sequences (RSSs) be found?

A

In the flanking regions of V-, D- and J-genes

71
Q

Why is it necessary that the RAG complex makes a hairpin after creating a dsDNA break?

A

To leave behind no reactive DNA damage that can further damage the DNA

72
Q

What is the process of hairpin opening by Artemis during NHEJ?

A
  1. Broken ends are recognized by KU-enzymes
  2. KU recruits DNA-PKcs
  3. DNA-PKcs recruits Artemis -> cleaves open hairpins
73
Q

Which enzymes are involved in strand ligation after hairpin opening by Artemis in NHEJ? (3)

A
  1. DNA ligase 4
  2. XLF
  3. XRCC4
74
Q

Which enzyme is responsible for n-nucleotide addition during V(D)J-recombination?

75
Q

When does Tdt add n-nucleotides?

A

Just before DNA-ligation during the NHEJ step of V(D)J-recombination

76
Q

What is the effect of a complete V(D)J-recombination defect?

77
Q

What is the presentation of SCID? (6)

A
  1. Early onset (>3 months of age)
  2. Repeated, severe & opportunistic infections
  3. Failure to thrive
  4. Chronic diarrhoea due to gastro-enteritis
  5. Lymphocytopenia
  6. Hypo-/agammaglobulinaemia
78
Q

Which to types of T-B- SCID can be identified?

A
  1. Non-radiosensitive T-B- SCID
  2. Radiosensitive T-B- SCID
79
Q

What is the cause of non-radiosensitive SCID?

A

Defect in lymphoid-specific DNA break initiation due to RAG1/RAG2 mutations

80
Q

What is the cause of radiosensitive SCID?

A

Defect in NHEJ machinery

81
Q

What is the effect of the defect in NHEJ machinery in radiosensitive SCID?

A

All body cells are sensitive to ionizing radiation

82
Q

How is radiosensitivity tested in SCID patients?

A

Exposing patient skin fibroblasts to ionizing radiation

83
Q

Why is it important to test SCID patients for radiosensitivity? (2)

A
  1. Non-radiosensitive SCID can be cured using HSCT, for which radiation & cell-killing agents are used -> dangerous for patients unable to perform DNA repair
  2. Non-immune cell defects will not be restored by HSCT
84
Q

Which gene defects are no. 1 and 2 for causing T-B- SCID?

A

Majority = RAG
2nd = Artemis

85
Q

What makes SCID exceedingly rare?

A

All genes involved in V(D)J-recombination are located on autosomal genes and rarely have a complete dysfunction

86
Q

In addition to radiosensitivity, what do radiosensitive SCID patients suffer from? (3)

A
  1. Severe imunodeficiency
  2. Neurological abnormalities
  3. Other abnormalities such as primordial dwarfism
87
Q

What makes that the neurological & immunological consequences of SCID occur along a spectrum of severity?

A

Residual enzyme function may somewhat reduce severity

88
Q

What is a frequently seen neurological abnormality in SCID patients?

A

Microcephaly

89
Q

What is an important prerequisite for good dsDNA break repair?

A

The strands of the break need to be held together until they can be ligated

90
Q

What are the steps of the process of holding DNA strands together in case of a dsDNA break? (3)

A
  1. MRN-complex formation -> holds ends together
  2. ATM-docking -> signalling hub for DNA damage
  3. Initiation of repair & shutdown of cell proliferation until damage is repaired
91
Q

Which factors make up the MRN complex, responsible for holding the strands of dsDNA breaks together? (3)

A
  1. MRE11
  2. RAD50
  3. NBN = Nibrin
92
Q

Which factors dock to the ATM DNA damage signalling hub? (2) Why is this useful knowledge?

A
  1. MDC1
  2. 53BP1

Antibodies against 53BP1 can be used to show unrepaired DNA ends

93
Q

What is Nijmegen Breakage syndrome?

A

Impaired DNA damage responses due to a biallelic mutation in the NBN gene

94
Q

What are the characteristics of Nijmegen Breakage syndrome? (7)

A
  1. Chromosomal instability
  2. Bird-like face
  3. Microcephaly
  4. Growth retardation
  5. Strong predisposition to malignancies
  6. Immunodeficiency due to lymphopenia
  7. Strong sensitivity to ionizing radiation
95
Q

What is the result of the NBN mutation in Nijmegen Breakage syndrome for V(D)J-recombination?

A

Loss of juxtapostion of RAG-induced breaks -> results in inefficient B-cell developmetn

96
Q

Which stages of B-cell maturation make up the majority of the B-cell component in Nijmegen Breakage syndrome patients? (2) Which components are low? (2)

A

High:
1. Pro-B
2. Pre-BI

Low:
1. Pre-BII
2. Immature B-cells

97
Q

Why are there still some immature B-cells in Nijmegen Breakage syndrome patients?

A

Loss of juxtaposition of RAG-induced breaks severely reduces recombination efficiency, but does not block it

98
Q

What is ataxia telangiectasia?

A

Chromosomal instability syndrome due to biallelic mutations in ATM gene

99
Q

What are the characteristics of ataxia telangiectasia? (5)

A
  1. Cerebellar deteroriation/ataxia
  2. Telangiectasia
  3. Strong predisposition to malignancies
  4. Variable immunodeficiency
  5. Severe sensitivity to ionizing radiation
100
Q

To what kind of infection are ataxtia telangiectasia patients especially sensitive?

A

Bacterial infection

101
Q

How is hypogammaglobulinaemia in ataxia telangiectasia patients treated?

102
Q

What are the two processes of the germinal centre response? Which is first? Where do they take place?

A

First: somatic hypermutation in the dark zone of the germinal centre
Second: class switch recombination in the light zone of the germinal centre

103
Q

How is somatic hypermutation performed?

A

Random mutations are added to the variable domain of the BCR

104
Q

What is required to initiate somatic hypermutation?

A

T-cell help

105
Q

Where is the majority of mutations in class switch recombination concentrated?

A

The complementarity determining regions of the variable domain of the BCR

106
Q

What happens when antigen-binding after somatic hypermutation is disrupted?

A

No antigen-internalization & presentation to T-cells -> no T-cell help -> apoptosis

107
Q

What happens when antigen-binding after somatic hypermutation is retained/increased?

A

Internalization & antigen -> presentation of MHCII -> T-cell help -> survival

108
Q

Into which cell types can B-cells differentiate after somatic hypermutation? (2)

A
  1. Plasmablast -> plasma cell
  2. Memory cell
109
Q

What happens during class switch recombination?

A

The constant domain of the antibody is replaced by that of another isotype

110
Q

What initiates class switch recombination, and determines the new isotype?

A

Presence of cytokines during the germinal centre reaction

111
Q

What is the most commonly used new isotype for B-cells in class switch recombination?

112
Q

Which constant regions can be foundin the BCR of naïve B-cells? What are their isotypes?

A

Cμ and Cδ, resulting in IgM and IgD

113
Q

What determines whether a naïve B-cell BCR is an IgM or IgD subtype?

A

Alternative splicing

114
Q

What is the switch region of the BCR?

A

The gene region to which new isotypes can be coupled

115
Q

To which constant domains (&isotypes) can B-cells switch during class switch recombination?

A

Cγ 1/2/3/4 -> IgG1/2/3/4
Cα 1/2 /-> IgA1/2
Cε -> IgE

116
Q

What are somatic hypermutation & class switch recombination both dependent on?

A

AID-dependent lesions

117
Q

What is AID? What does it do?

A

Activation-induced cytidine deaminase -> deaminates cytodines, turning them into uracil -> causes mismatch

118
Q

What is the concentration of AID-dependent lesions in somatic hypermutation? What does this result in?

A

Low concentration of lesions, resulting in point mutations which are randomly repaired -> causes mutations

119
Q

What is the concentration of AID-dependent lesions in class switch recombination? What does this result in?

A

High amount of AID target sites causes high accumulation of lesions -> dsDNA breaks

120
Q

How are low-density AID-dependent laesiosn repaired in somatic hypermutation? (3) What do they each result in?

A
  1. No repair -> DNA gets repaired uring next proliferation, where U gets seen as T. Result: CG-base-pair transitions into A-T
  2. Base-excision repair -> abasic site gets removed, a random nucleotide can be moved in.
    Result: mostly repaired with a C, but can also be other nucleotides.
  3. Mismatch repair -> whole stretch of DNA removed & reconstructed based on the complementary strand.
    Result: MMR = error-prone -> frequent introduction of mutations
121
Q

What allows AID-induced dsDNA breaks in class switch recombination to be repaired by NHEJ?

A

Switch regions of BCR genes have high homology -> allows for switch using alternative isotypes

122
Q

Which disease is an example of a disease that results from a defect in class switch recombination?

A

Hyper-IgM syndrome

123
Q

What causes hyper-IgM syndrome? What is its mechanism?

A

UNG deficiency
UNG = necessary to excise U in BER -> causes defect in class switch recombination

124
Q

What are the characteristics of hyper-IgM syndrome?

A
  1. Patients are susceptible to bacterial infections
  2. Normal/increased IgM
  3. Low/absent IgG, IgE & IgA
125
Q

What is an additional problem of the antibodies in hyper-IgM syndrome?

A

Impaired affinity maturation -> low affinity antibodies

I&I WC2 (25 decks)

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